Lesinurad, or 2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetic acid, is marketed in the United States as ZURAMPIC®, and is indicated, in combination with a xanthine oxidase inhibitor, for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone. Lesinurad has the following structural formula:

One method of preparing Lesinurad is described in WO 2009/070740 A2, which discloses a family of compounds that are useful in decreasing uric acid levels. Similar methods of preparing Lesinurad are disclosed in WO 2014/008295 A1 and CN 105566237 A. In this method, which is depicted in Scheme 1, Lesinurad is prepared from starting material (A) by reaction with a methyl haloacetate, followed by diazotization and displacement with bromide to yield the compound of Formula (C), which is further hydrolysed to yield Lesinurad (1).

In WO 2009/070740 A2 and CN 105566237 A, bromination is conducted using excessive amounts of sodium nitrite, a strong oxidant, as well as a number of toxic and corrosive reagents, including tribromomethane and dichloroacetic acid. An alternative bromination is described in WO 2014/008295 A; however, the process uses equimolar amounts of cuprous bromide as the bromide source, which will result in higher costs when conducted on a commercial scale owing to the high cost of this reagent, as well as the waste disposal costs associated with the use of heavy metal reagents such as copper. Furthermore, the commercial application of this process is further hindered by the preparation of the compound of Formula (A), which is reported to be lengthy, requiring purification steps and multiple isolations of the same compound to produce the compound of Formula (A) having sufficient quality for use in the preparation of Lesinurad.
A second strategy for the preparation of Lesinurad is described in WO 2014/008295 A1 and WO 2015/054960 A1. In this approach, Lesinurad is prepared from starting material (D) by reaction with a methyl haloacetate followed by direct bromination of the triazole (E) to yield (C), which is hydrolyzed to provide Lesinurad (1) as shown in Scheme 2. A similar method for preparing Lesinurad is described in WO 2014/198241 A1, wherein analogues of triazole (E) having a variety of thioglycolate ester and amide sidechains are brominated.

While this approach overcomes some of the problems associated with bromination of the compound of Formula (B), according to optimization results reported in WO 2014/008295 A1, the range of conditions available to achieve successful bromination in high purity is limited.
In alternative processes for the preparation of Lesinurad, such as those reported in CN 105017168 A and CN 105153056 A, installation of the thioglycolate side chain occurs by first displacing a hydroxyl or diazonium group (following diazotization of the amine) on the triazole ring of compounds (F) or (G), respectively, followed by addition of the thioglycolate side chain using methyl thioglycolate. However, methyl thioglycolate is a malodorous substance that is preferably avoided in processes conducted on an industrial scale.

Many of the reported processes for the preparation of Lesinurad suffer from the use of toxic, corrosive, malodorous and/or expensive reagents, in some cases generating waste that requires special and costly disposal procedures. Additionally, the syntheses of some of the raw materials, such as the compound of Formula (A), are reported to be lengthy and complicated. These factors limit the practicality of using the known processes to prepare Lesinurad on a commercial scale. Owing to the drawbacks of the existing processes for the preparation of Lesinurad, there remains a need for improved processes for the preparation of Lesinurad, and the intermediates used in such preparations, that are more amenable to scale-up and use on a commercial scale.